Oxtoation of barbituric acid to



Patented July 27, l1948 UNITED' STATE s PATENT oFFlC-Ef f No Drawing.

' My invention relatesto'a'newniethod of making alloxan by direct oxidationof barbituric acid. The *methodr is of interest Vbecause alloxan has in recent lyears become an important intermediate forfthe synthesis` of riboflaviii.l

By direct `oxidation I mean thatbarbituric acid itself and not as' heretoforev aderivative thereof is" used I'as initial material" which through the "action of'Man" oxidizingfagent isy converted into `alloxanaccordinvg to the formula to'alloxanhas heretofore been recorded in litera- .Fischer ,and Helfferich (Anleitung,zur-Darste1 lung organischer Praeparate,. th ed., page66, Braunschweig; 1922).` used potassium chlorate and hydrochloric lacidl for Vthe same reaction. Alloxantin, xanthin, uramil and thiouramil like- Wise can be oxidized to alloxan (Whler, Liebig, Ann., 1838, 26, 256; Fischer, Ann., 1882, 215, 310; Fischer, Ach, Ann., 1895, 288, 160); it is obvious that the starting materials used in these procedures are too difcultly available to render any one of them suitable for a large scale production.

In the past, several methods have been used for the technical preparation of alloxan. The oldest method is that of oxidizing uric acid which, however, has no practical importance today, since uric acid is much too expensive for technical purposes. A subsequently developed method is based on the oxidation of uramil, already mentioned. This procedure starts with barbituric acid, which is converted into nitrosobarbituric acid and reduced to uramil, which is then oxidized. The method requires four steps. It was abandoned when Biilmann and Berg (Ben, 1930, 63, 2201) devised a new method of preparing alloxan from barbituric acid, involving only two steps, namely,

ApplicationNovember 20,1944, o 2 i, o sria1No.5s4,41s u l `nomine. (c1. 26o- 257) 2 the formation of .benzalbarbituric acid and `its oxidation Withchromic acid. Up lto date, this is the simplest and cheapest manufacturing process for alloxan. However, Biilmann and Bergufail to recognize the possibility of direct oxidation of barbituricacid. o Ihave now discovered that barbituric acid itself can directly be oxidized to alloxan by reacting it with an oxidizing agent a 'liquid reaction medium. The synthesis of alloxan,v lfrom barbituric acid' is thusreduced to one` single step'. I have found that this method ishighly advantageous in contrastto` the Biilmann-Berg proL cedure, because one essential step of that procedure is entirely omitted, since the`conversion of the barbituric acid into `its benzal derivative prior to oxidation is no longer requiredn The cost of theV expensive benzaldehyde is thereby saved.` The use of suitable oxidizing agents, such as chromic acid, chloric acid and manganese dioxide, is illustrated in the attached examples. The direct chromic acid oxidation of V,barbituric acid has proven particularlyuseful in contrast to the same oxidationof benzalbarbituric` acid. It requires, only qtWo-thirdsof the, Va1r1 ount,.`of chromic acid. .consumed` in the Voxidation of benzalbarbituric acid;` this holds trueofalldi'rect oxidatlfOn processes'` of ibarbituric acid sitio no oxidation agent is` needed to oxidizev a side` chain,

separation of the alloxancontain ,only negligible amounts,` of .by-products `,besides chromium acetate,V whereas lthe mother ,liquors obtfairiegl,acf-

cording .to the. procedure ,of .Biilmann and 'Berg hold the total amount 'ofbenzoic,acidioriginating from the benzal group of the benzalbarbiturc acid. Since this benzoic acid is present as a complex chromium salt, the regeneration of the chromium presents diilculties which are avoided in the new procedure.

Chloric acid has the advantage that it is a comparatively cheap and yet powerful oxidant. Oxidation with chloric acid is preferentially carried out in the presence of a low proportion of vanadium pentoxide, as shown hereinafter in Example 2. The vanadium pentoxide functions as a catalyst in the reaction. It can be employed in aqueous solution. A solution of alloxan is thus obtained which can be used as such for further reactions. If it is desired to isolate the alloxan from the solution, it is possible to reduce the alloxan to a less soluble derivative such as alloxantin, which can easily be isolated and reconverted into alloxan by a simple procedure.

3 The following examples illustrate my invention:

E'ample 1 128 parts of |barbituric acid containing 2 moles of water .of ,crystallization are slowly added to a solutionlof 1140 par-ts .of chromium trioXide, also referred to in the art as chrornic acid, in a mixture of 800 parts of glacial acetic acid and 80 parts of water. The mixture is stirred vigorously. The addition of the barbituricacidiis made such a way that the temperature of the reaction mixture does not exceed 55 ,C. After complete addition the mixture is stirred iforoniemore hour at 55 to 60 C. Alloxan starts slowly :to Separate. The mixture is cooled to ,|5 and filtered. 104 g. of alloxan are directly obtained (811% yoi theoretical yield).

Example 2 4ffliparizs of harbituric acid,.220 parts of sodium chlorate and 1 `part .of vanadium pentoxide are .stirred at room temperature .with 2500 parts of water. A solution of 115 ,parts of sulfuric acid r95%) `in y1000 parts .of water is Islowly added over a period of several hours. The temperature rises slowly, The .addition of the sulfuric lacid is regulated in such .a way `that the temperature .does not exceed 45 to 50. The .barbituric acid goes slowly into solution and `a precipitate `separatesslowly. This precipitate is filtered off, the .filtrate is ychilled to .0 land l.a solution 0f 5100 parts oristannolls chloride in500 partsof concentrated hydrochloric acid is vadded with stirring at Asuch aratethat. the `temperature does not rise .above +3". `Allcxantin starts to precipitate after a `short while. When vall the ,stannous ,chloride A.soli-wien .is added, the. alloxantin is filtered jimmediately', v.washed withy ice cold .dilute hydrochloric 4acid and ice cold Water. By recrystallization `from boiling. water 1pure .alloxantin ris obtained. '-Iihe yield amounts to .about 3,50 parts yi( 33% l,of vthe theoretical). f

Example 3 l Fifty-two parts of manganese dioxide, 500'parts of water, and 80 parts of sulfuric acid 95% are ,stirred at room temperature. v38.4 parts of bar- `bituric acid are added in about portions over a period of several hours. 'Ihe well-stirred mix- ,i

"filtered ofi. The mother liquor is reduced with a solution of stannous chloride in hydrochloric acid at 0. Aglloxantinseparates and can be isoiatedhyitraiion.

What I claim is:

1. The process of preparing alloxan which comprises mixing and reacting barbituric acid with an oxidizing agent selected from the group consisting of Vchromic acid, chloric acid and man- ,ganeseidioxide in an arcidmedium so .as to produce alsloxan. v

2. The process of claim 1 in which chromic acid is used as the oxidizing agent.

.3. The prDCSs pf claim 1 in which -chloric acid is used as theoxidizing agent.

4. The process of claim 1 in which the oxidiz- -ingiagent employed is manganese dioxide.

The-@process which comprises mixing and reacting harbituricacid with chromium trioxide in .acetic acdrSoas toproduce alloxan.

'6. The process of claim 5 in which the temperature is maintained below about C.

"The process which comprises mixing andreacting barbituric acid by adding an aqueous solution of sodium chl-crate to a mixture of barbituric acid and ldilute sulfuric acid coritaining aasmall .amount of vanadium gpentoxide .so :as to produce alloxan.

8. The process of claim 7 :in `which thetempcnyature is maintained below about .60 C.

9. The process which comprises mixing-and Jrc- .acting bar-bituric acidl with manganese *dioxide in :the presence of dilute sulfuric .acid .in aqueous medium .so .as -to producefal-loxan.

10. The process which comprises Vmixing and reacting barbituric acid in an aqueous solution with an oxidizing agent selected from the group consisting of `chromic acid, ichloiiciacidf and manganese dioxide so as to produce alloxan, reducing the alloxan to alloxantin in the4 same solution without the separation of the alloxan from `the solution in `which :it-is formed, land. separating the farlcxantin as a crystalline .material from the aqueous solution.

11. Theprocess of -claim 110 in whichtheireducy'tion is carried out-by ,means'of stannous chloride and `hydrochloric acid.

REFERENCES (JI-TED 'The following .reterences are lof record indthe `file of this patent: v

OTHER 'REFERENCES Organic"Synthesis, vol. 23, M13-1 (f1'943)`;.1bid., vol.21,pp.f58 :(1941). l

Baeyer; .Liebigs Annalen,'vol;1-130,p. 140. Britz, Heyn, Berichte, vol. 52, p. :1302, 

